Ten years to ten days: French startup revolutionizes early diagnosis of endometriosis with a saliva test 

Ziwig revolutionizes endometriosis diagnosis

A condition that affects around 190 million women and girls worldwide, according to the World Health Organization, endometriosis is a chronic, difficult-to-treat disease that causes debilitating pelvic pain. Often misdiagnosed as irritable bowel syndrome (IBS) and sometimes dismissed as menstrual cramps, the diagnosis of endometriosis can take around 10 years, raising the severity of the condition. But this is bound to change as French startup Ziwig has come up with a way to diagnose this disease in 10 days.

Based in the city of Lyon, Ziwig, a biotech that was founded in 2019, aims to drastically cut the diagnostic delay for people with endometriosis to be able to receive the care they need as early as possible with the help of a saliva test.

What makes endometriosis so hard to diagnose?

When tissues similar to those found in the lining of the uterus grow outside the uterus, affecting the ovaries, fallopian tubes and the pelvis, it is characterized by severe pain during sex and one’s periods. This is because endometrial-like tissue, which thickens and bleeds with every menstrual cycle, instead of shedding, gets trapped in the ovaries, sometimes leading to the formation of cysts. This further results in inflammation and the accumulation of scar tissue, which causes pelvic pain and elevates the risk of infertility.

While these symptoms may be indicative of endometriosis, it’s still not easy to diagnose the disease. According to Andrew Spiers, head of Clinical Innovation at Ziwig, current diagnostic measures include patients filling out a questionnaire on symptoms that they’ve experienced. Spiers claims that although it is important to note the patient’s history, it is not specific enough to diagnose the condition.

One way to detect the presence of unusual tissue growth is through magnetic resonance imaging (MRI) scans and ultrasounds. However, if the tissues are tiny and form on the surface of the organs and not inside them, scans may not detect them. In fact, according to European guidelines, negative results from scans do not rule out the disease.

That leaves many with the option of having to undergo a surgical procedure like laparoscopy. This involves the use of a camera inside the abdomen through which the insides of the gut and pelvis are relayed onto a screen to detect endometrial-like tissues. While this may perform as a diagnostic tool for endometriosis, many shy away from being operated on as it is a “hugely invasive process,” explained Spiers.  

How does Ziwig’s Endotest work?

This is where Ziwig’s saliva-based endometriosis test comes in. People are required to spit into a tube that is sent to a laboratory that will test for endometriosis. This is done by examining the microRNA in a saliva sample. 

MicroRNAs (miRNA) are short, single strand nucleotides that are involved in regulating gene expression. These link to messenger RNAs (mRNA) – which have garnered attention in Covid vaccines – to silence genes, meaning that proteins that are typically produced by mRNAs, will no longer be produced.

Having evaluated over 2,600 miRNAs in patients, Ziwig was able to design a signature of 109 miRNA leveraging the capabilities of artificial intelligence. In a study published in The New England Journal of Medicine last month, it was found that Ziwig’s Endotest, which assessed the saliva of women between the ages of 18 and 43, showed over 95% sensitivity and specificity. Moreover, it was validated in one of the largest clinical trials for endometriosis, across hospitals in France, and was also found to function properly at room temperature. 

“One of the main advantages of the Endotest, is that it’s able to replace diagnostic laparoscopy,” said Spiers. “And then they (patients) would be able to not have invasive examinations and rather do the Endotest… There’s a long delay between when a practitioner would do imaging and then they might try probabilistic, what we call empirical treatment, to see if it helps. And in some cases, patients don’t want to take hormonal treatment without having a diagnosis. And that’s something which is completely understandable. So it also gives practitioners the possibility to provide patients with the diagnosis before giving patients medication to take.”

As the Endotest is a prescription diagnostic tool rather than a screening method, it is recommended to be used after imaging is carried out, according to practitioners. 

“We feel that patients should have a clinical examination with a practitioner who will look at the signs and symptoms of disease, and they should have imaging – either ultrasound or MRI. And if, after this, there’s a very clear cut diagnosis, there is endometriosis, then practitioners can move forward with treatment. Unfortunately, in the majority of cases of imaging, there isn’t a clear cut diagnosis,” said Spiers who expressed that the test’s reliability could solve issues surrounding diagnostic delay, and patients can know once and for all whether they have endometriosis, and then proceed with therapy.

Another drawback to current diagnostic measures that the Endotest aims to tackle is the inability of other tests to accurately detect all forms of the disease. For instance, there are times when laparoscopy surgery does not pick up early stages as well as superficial peritoneal forms of endometriosis, which is the most common type of the disease as it accounts for 80% of all endometriosis diagnoses. It is formed by the development of a shallow lesion along the peritoneum, which is the membrane that lines the abdomen. Other kinds of endometriosis include endometrioma – caused by cysts in the ovaries – and deep endometriosis – which infiltrates deep within organs, invading them.

Sometimes, in the case of superficial endometriosis, the surgeon might take a sample that may be just a few centimeters away from where there is a lesion. And so, Ziwig’s test is designed to address this issue with its improved accuracy compared to other diagnostic tools.

“Endometrioma can be found reliably using pelvic ultrasound, whereas superficial disease is far more difficult to find. So again, the complexity of the disease adds to the difficulty of the diagnosis. And, in some cases, imaging does suffice and that’s why we say that patients should follow this pathway of doing imaging. But, again, unfortunately, most of the time, it’s not enough for a sure diagnosis to be reached,” said Spiers.

Endometriosis care: need for swifter diagnosis 

As patients are sometimes offered treatment without receiving an official diagnosis, Spiers explained that the Endotest can provide a definitive answer to whether they have endometriosis or not.

“Patients who have symptoms, they don’t know what’s going on. In some cases, they’ve been given treatment on an empirical basis, they’ve been given treatment without having diagnosis. Whereas, the Endotest diagnosis, it provides patients with an answer… If they don’t want to take an empirical treatment, it means a practitioner can give them treatment with the diagnosis which has been done. It also means that care pathways can be adapted very, very quickly, at an early stage, to help patients because the objective of treatment is to stop the evolution of the disease. So, it actually means that if we’re finding the disease earlier, we can stop it from evolving to late stage disease.”

Although a cure is yet to be found, some symptoms of endometriosis are treatable, especially when caught early on. Many people are prescribed hormone therapy – which is the contraceptive pill – to halt the production of estrogen in the body as the hormone stimulates the growth of endometriosis tissue. Surgery is also performed to destroy the tissues in order to ease symptoms.

Ziwig’s plans for the future

Currently available in parts of Europe like the U.K., Italy, Germany, Switzerland as well as in Saudi Arabia and the United Arab Emirates, the Endotest will soon be commercialized in Hungary, Belgium, Luxembourg, Kuwait, Qatar, and Israel. To add to that, the company is looking to develop a test that can tell what kind of endometriosis a patient has, as Ziwig focuses on expanding diagnostic options for all forms of endometriosis.

“This will be a first step into developing a really personalized treatment. Because if we know exactly what biological subtype a patient has, we can link how these biological subtypes respond to different treatment regimens. So, the patients will then have, not only a diagnosis, but an indicator of the optimal treatment path for them. So this would have incredible added value,” said Spiers.

While endometriosis has been an understudied and underfunded disease for many years, Spiers recounted that this is steadily improving now. “So endometriosis has, for many years been, I think in some respects, under researched. And today, we see more and more research being done, which is fantastic. I would say that research is definitely accelerating in the field and what needs to be done is being done, but again, we need to find targeted and personalized treatment solutions for patients.”

As the disease affects those right from adolescence until around menopause, endometriosis can be life-altering for patients, according to Spiers.

“It’s a disease which has a huge impact on the quality of life of patients. Symptoms are the most acute at times when they’re making decisions for their studies, for their personal lives, for their professional lives,” said Spiers. “And when patients describe the pain, they describe it as being really hugely intense. So the Endotest has the huge potential to help patients because today, the average diagnostic delay between when a patient will start feeling symptoms until when a diagnosis is reached, is years. In some countries, it’s five years, in some countries, it’s as many as 10 to 12 years. So, we’re basically reducing a diagnostic delay from 10 years to 10 days. And this means that patients who are suffering are able to get adapted care. And this is really hugely important for us.”

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